Acute heart failure in elderly patients: worse outcomes and differential utility of standard prognostic variables. Insights from the PROTECT trial.

AIMS: Previous heart failure (HF) trials suggested that age influences patient characteristics and outcome; however, under-representation of elderly patients has limited characterization of this cohort. Whether standard prognostic variables have differential utility in various age groups is unclear. METHODS AND RESULTS: The PROTECT trial investigated 2033 patients (median age 72 years) with acute HF randomized to rolofylline or placebo. Patients were divided into five groups based on the quintiles of age: ≤59, 60-68, 69-74, 75-79, and ≥80 years. Baseline characteristics, medications, and outcomes (30-day death or cardiovascular/renal hospitalization, and death at 30 and 180 days) were explored. The prognostic utility of baseline characteristics for outcomes was investigated in the different groups and in those aged <80 years vs. ≥80 years. With increasing age, patients were more likely to be women with hypertension, AF, and higher EF. Increased age was associated with increased risk of 30- and 180-day outcomes, which persisted after multivariable adjustment (hazard ratio for 180-day death = 1.17; 95% confidence interval 1.11-1.24 for each 5-year increase). The prognostic utility of baseline characteristics such as previous HF hospitalization and serum sodium, systolic blood pressure, and NYHA class was attenuated in the elderly for the endpoint of 180-day mortality. An increase in albumin was associated with a greater reduction in risk in patients aged ≥80 years vs. <80 years. CONCLUSIONS: In a large trial of acute HF, there were differences in baseline characteristics and outcomes amongst patients of different ages. Standard prognostic variables exhibit different utility in elderly patients.

Predictors of postdischarge outcomes from information acquired shortly after admission for acute heart failure: a report from the Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) Study.

BACKGROUND: Acute heart failure is a common reason for admission, and outcome is often poor. Improved prognostic risk stratification may assist in the design of future trials and in patient management. Using data from a large randomized trial, we explored the prognostic value of clinical variables, measured at hospital admission for acute heart failure, to determine whether a few selected variables were inferior to an extended data set. METHODS AND RESULTS: The prognostic model included 37 clinical characteristics collected at baseline in PROTECT, a study comparing rolofylline and placebo in 2033 patients admitted with acute heart failure. Prespecified outcomes at 30 days were death or rehospitalization for any reason; death or rehospitalization for cardiovascular or renal reasons; and, at both 30 and 180 days, all-cause mortality. No variable had a c-index>0.70, and few had values>0.60; c-indices were lower for composite outcomes than for mortality. Blood urea was generally the strongest single predictor. Eighteen variables contributed independent prognostic information, but a reduced model using only 8 items (age, previous heart failure hospitalization, peripheral edema, systolic blood pressure, serum sodium, urea, creatinine, and albumin) performed similarly. For prediction of all-cause mortality at 180 days, the model c-index using all variables was 0.72 and for the simplified model, also 0.72. CONCLUSIONS: A few simple clinical variables measured on admission in patients with acute heart failure predict a variety of adverse outcomes with accuracy similar to more complex models. However, predictive models were of only moderate accuracy, especially for outcomes that included nonfatal events. Better methods of risk stratification are required. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00328692 and NCT00354458.

Renal function trajectories and clinical outcomes in acute heart failure.

BACKGROUND: Prior studies have demonstrated adverse risk associated with baseline and worsening renal function in acute heart failure, but none has modeled the trajectories of change in renal function and their impact on outcomes. METHODS AND RESULTS: We used linear mixed models of serial measurements of blood urea nitrogen and creatinine to describe trajectories of renal function in 1962 patients with acute heart failure and renal dysfunction enrolled in the Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function study. We assessed risk of 180-day mortality and 60-day cardiovascular or renal readmission and used Cox regression to determine association between renal trajectories and outcomes. Compared with patients alive at 180 days, patients who died were older, had lower blood pressure and ejection fraction, and higher creatinine levels at baseline. On average for the entire cohort, creatinine rose from days 1 to 3 and increased further after discharge, with the trajectory dependent on the day of discharge. Blood urea nitrogen, creatinine, and the rate of change in creatinine from baseline were the strongest independent predictors of 180-day mortality and 60-day readmission, whereas the rate of change of blood urea nitrogen from baseline was not predictive of outcomes. Baseline blood urea nitrogen>35 mg/dL and increase in creatinine>0.1 mg/dL per day increased the risk of mortality, whereas stable or decreasing creatinine was associated with reduced risk. CONCLUSIONS: Patients with acute heart failure and renal dysfunction demonstrate variable rise and fall in renal indices during and immediately after hospitalization. Risk of morbidity and mortality can be predicted based on baseline renal function and creatinine trajectory during the first 7 days. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00328692 and NCT00354458.

Assessment of drug-induced increases in blood pressure during drug development: report from the Cardiac Safety Research Consortium.

This White Paper, prepared by members of the Cardiac Safety Research Consortium, discusses several important issues regarding the evaluation of blood pressure (BP) responses to drugs being developed for indications not of a direct cardiovascular (CV) nature. A wide range of drugs are associated with off-target BP increases, and both scientific attention and regulatory attention to this topic are increasing. The article provides a detailed summary of scientific discussions at a Cardiac Safety Research Consortium-sponsored Think Tank held on July 18, 2012, with the intention of moving toward consensus on how to most informatively collect and analyze BP data throughout clinical drug development to prospectively identify unacceptable CV risk and evaluate the benefit-risk relationship. The overall focus in on non-CV drugs, although many of the points also pertain to CV drugs. Brief consideration of how clinical assessment can be informed by nonclinical investigation is also outlined. These discussions present current thinking and suggestions for furthering our knowledge and understanding of off-target drug-induced BP increases and do not represent regulatory guidance.

The predictive value of short-term changes in hemoglobin concentration in patients presenting with acute decompensated heart failure.

OBJECTIVES: The study sought to investigate the clinical correlates and prognostic role of anemia and changes in hemoglobin in patients hospitalized for acute decompensated heart failure (AHF). BACKGROUND: Anemia is related to a poor outcome in patients with heart failure. In addition, an increase in hemoglobin during hospitalization might be a sign of effective decongestion and therefore related to improved outcome. METHODS: This is a post hoc analysis of the PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) study in 1,969 patients with AHF and mild to moderate impaired renal function. Hemoglobin levels were measured daily for the first 4 days and at day 7. The endpoint was 180-day all-cause mortality. RESULTS: Anemia at baseline was observed in 50.3% of the patients. During follow-up, 359 patients (18.2%) died. Hemoglobin increased in 69.1% and was associated with a better renal function at baseline and more weight loss, but was associated with a deterioration of renal function (p = 0.01), whereas total dose diuretics was lower in patients with hemoconcentration (p < 0.01). Interaction analysis showed that greater weight loss and better baseline renal function were associated with a more rapid increase in hemoglobin concentration (p < 0.01 for both). The absolute change in hemoglobin (g/dl) independently predicted outcome (hazard ratio: 0.66; 95% confidence interval: 0.51 to 0.86; p = 0.002), whereas baseline hemoglobin levels did not. CONCLUSIONS: Patients with AHF and preserved renal function are decongested better, as shown by an increase in hemoglobin. A rapid increase in hemoglobin during the first week is independently associated with a favorable outcome, despite a slight decrease in renal function.

The PROTECT in-hospital risk model: 7-day outcome in patients hospitalized with acute heart failure and renal dysfunction.

AIMS: In patients with acute heart failure (AHF), early worsening heart failure (WHF) predicts a significant proportion of post-discharge readmissions and mortality. We aimed to identify the predictors of 7-day heart failure events or death in patients hospitalized with AHF. METHODS AND RESULTS: A predictive model and risk score for the short-term primary composite endpoint of 7-day death, HF rehospitalization, or WHF was created using variables collected within 24 h of admission from patients with complete data (n = 2015) enrolled in the PROTECT trial of AHF patients. The 7-day composite was experienced by 294 patients (14.6%), with a mortality rate of 1.8% (n = 37), HF rehospitalization rate of 0.5% (n = 9), and WHF rate of 13.1% (n = 264). In multivariable analyses, the strongest predictor of short-term morbidity and mortality was higher blood urea nitrogen (BUN) concentration. Additional independent predictors of a worse outcome were lower serum albumin, cholesterol, and systolic blood pressure, as well as higher heart rate and respiratory rate. Model coefficients were converted to an additive risk score for predicting the 7-day composite endpoint with a total point range of 0-100. The risk score allowed discrimination of a wide spectrum of risk (4.8% risk with score ≤35, to 28.7% risk with score >55). CONCLUSIONS: Using the PROTECT 7-day risk model and score, the main determinants of an adverse outcome for AHF patients included impaired metabolic status, neurohormonal activation, and reduced cardiac performance, gauged by BUN, serum albumin and cholesterol levels, systolic blood pressure, heart rate, and respiratory rate.

The safety of an adenosine A(1)-receptor antagonist, rolofylline, in patients with acute heart failure and renal impairment: findings from PROTECT.

BACKGROUND: Adenosine exerts actions in multiple organ systems, and adenosine receptors are a therapeutic target in many development programmes. OBJECTIVE: The aim of this analysis was to evaluate the safety of rolofylline, an adenosine A(1)-receptor antagonist, in patients with acute heart failure. METHODS: The effect of rolofylline was investigated in patients hospitalized for acute heart failure with impaired renal function. Intravenous rolofylline 30 mg or placebo was infused over 4 hours daily for up to 3 days. Adverse events (AEs) and serious AEs (SAEs) were recorded from baseline through 7 and 14 days, respectively, and clinical events were adjudicated through 60 days. RESULTS: Of 2033 patients enrolled, 2002 received study drug randomized 2 : 1 to rolofylline or placebo. Rolofylline and placebo were associated with a similar risk of pre-specified groups of AEs or SAEs, other than selected neurological events. Investigator-reported seizures occurred in 11 (0.8%) rolofylline-treated patients and zero patients receiving placebo (p = 0.02). Stroke occurred in 21 (1.6%) patients assigned to rolofylline compared with 3 (0.5%) placebo-treated patients through 60 days with a greater risk for stroke in the rolofylline group (hazard ratio 3.49; 95% CI 1.04, 11.71; p = 0.043). There was no temporal relation to rolofylline administration and no specific stroke subtype or clinical characteristics that predicted stroke in the rolofylline group. CONCLUSIONS: Rolofylline treatment was associated with an increased seizure rate, an anticipated complication of A(1)-receptor antagonists. An unanticipated, disproportionate increase in strokes in the rolofylline-treated patients emerged, although no clear temporal relation, aetiology, stroke subtype or interacting factor suggestive of a causal mechanism was identified. Further research into stroke as a potential complication of adenosine-modulating therapies is required. Additionally, this study underscores the value of longer follow-up durations for AEs, even for agents with short treatment periods, such as in acute heart failure.

Effects of the adenosine A1 receptor antagonist rolofylline on renal function in patients with acute heart failure and renal dysfunction: results from PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function).

OBJECTIVES: This study sought to assess the effects of rolofylline on renal function in patients with acute heart failure (AHF) and renal dysfunction randomized in PROTECT (Placebo-Controlled Randomized Study of the Selective A(1) Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). BACKGROUND: Small studies have indicated that adenosine A(1) receptor antagonists enhance diuresis and may improve renal function in patients with chronic heart failure or AHF. METHODS: A total of 2,033 patients with AHF, volume overload, estimated creatinine clearance between 20 and 80 ml/min, and elevated natriuretic peptide levels were randomized (2:1) within 24 h of hospital presentation to rolofylline 30 mg/day or intravenous placebo for up to 3 days. Creatinine was measured daily until discharge or day 7 and on day 14. Persistent worsening renal function was defined as an increase in serum creatinine ≥0.3 mg/dl at both days 7 and 14, or initiation of hemofiltration or dialysis or death by day 7. RESULTS: At baseline, mean ± SD estimated creatinine clearance was 51.0 ± 20.5 ml/min in the placebo group and 50.4 ± 20.0 ml/min in the rolofylline group. Changes in creatinine and estimated creatinine clearance were similar between placebo- and rolofylline-treated patients during hospitalization and at day 14. After 4 days, mean body weight was reduced by 2.6 and 3.0 kg in placebo and rolofylline patients, respectively (p = 0.005). Persistent worsening renal function occurred in 13.7% of the placebo group and 15.0% of the rolofylline group (odds ratio vs. placebo: 1.11 [95% confidence interval: 0.85 to 1.46]; p = 0.44). CONCLUSIONS: In this large, phase III clinical trial, the adenosine A(1) receptor antagonist rolofylline did not prevent persistent worsening renal function in AHF patients with volume overload and renal dysfunction. (A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function [PROTECT-1], NCT00328692; and [PROTECT-2], NCT00354458).

Early dyspnoea relief in acute heart failure: prevalence, association with mortality, and effect of rolofylline in the PROTECT Study.

AIMS: Dyspnoea and pulmonary and/or peripheral congestion are the most frequent manifestations of acute heart failure (AHF) and are important targets for therapy. We have assessed changes in dyspnoea, their relationship with mortality, and the effects of the adenosine A1 receptor antagonist rolofylline on these endpoints in patients enrolled in the PROTECT trial. METHODS AND RESULTS: PROTECT was a prospective, double-blind, placebo-controlled study assessing the effect of rolofylline in patients hospitalized for AHF with dyspnoea, fluid overload, increased plasma natriuretic peptides, and mild-to-moderate renal dysfunction. Early dyspnoea relief, prospectively defined as moderately or markedly better dyspnoea at both 24 and 48 h after the start of study drug administration, occurred in 49.8% of the patients. Early dyspnoea relief was associated with greater weight loss and with reduced mortality at Days 14 and 30 [hazard ratio (HR) 0.28, 95% confidence interval (CI): 0.15, 0.50; and 0.35, 95% CI: 0.22, 0.55, respectively]. Rolofylline administration was associated with an increase in the proportion of patients showing early dyspnoea relief (HR 1.30; 95% CI: 1.08, 1.57) and with a numerically lower mortality at 14 and 30 days, largely driven by the mortality due to HF [at 30 days, HR (95% CI, P-value): 0.65 (0.38-1.10, P= 0.107)]. Rolofylline did not reduce episodes of in-hospital worsening HF or post-discharge re-admissions, nor did it improve survival at 60 or 180 days. CONCLUSION: The present analysis from PROTECT demonstrated that more weight loss was associated with early dyspnoea relief and reduced short-term mortality.

Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure.

BACKGROUND: Worsening renal function, which is associated with adverse outcomes, often develops in patients with acute heart failure. Experimental and clinical studies suggest that counterregulatory responses mediated by adenosine may be involved. We tested the hypothesis that the use of rolofylline, an adenosine A1-receptor antagonist, would improve dyspnea, reduce the risk of worsening renal function, and lead to a more favorable clinical course in patients with acute heart failure. METHODS: We conducted a multicenter, double-blind, placebo-controlled trial involving patients hospitalized for acute heart failure with impaired renal function. Within 24 hours after presentation, 2033 patients were randomly assigned, in a 2:1 ratio, to receive daily intravenous rolofylline (30 mg) or placebo for up to 3 days. The primary end point was treatment success, treatment failure, or no change in the patient's clinical condition; this end point was defined according to survival, heart-failure status, and changes in renal function. Secondary end points were the post-treatment development of persistent renal impairment and the 60-day rate of death or readmission for cardiovascular or renal causes. RESULTS: Rolofylline, as compared with placebo, did not provide a benefit with respect to the primary end point (odds ratio, 0.92; 95% confidence interval, 0.78 to 1.09; P=0.35). Persistent renal impairment developed in 15.0% of patients in the rolofylline group and in 13.7% of patients in the placebo group (P=0.44). By 60 days, death or readmission for cardiovascular or renal causes had occurred in similar proportions of patients assigned to rolofylline and placebo (30.7% and 31.9%, respectively; P=0.86). Adverse-event rates were similar overall; however, only patients in the rolofylline group had seizures, a known potential adverse effect of A1-receptor antagonists. CONCLUSIONS: Rolofylline did not have a favorable effect with respect to the primary clinical composite end point, nor did it improve renal function or 60-day outcomes. It does not show promise in the treatment of acute heart failure with renal dysfunction. (Funded by NovaCardia, a subsidiary of Merck; ClinicalTrials.gov numbers, NCT00328692 and NCT00354458.).

Design and rationale of the PROTECT study: a placebo-controlled randomized study of the selective A1 adenosine receptor antagonist rolofylline for patients hospitalized with acute decompensated heart failure and volume overload to assess treatment effect on congestion and renal function.

BACKGROUND: Current treatment for acute decompensated heart failure (ADHF) is associated with incomplete resolution of symptoms and signs, recurrent symptoms of heart failure in-hospital and after discharge and high mortality. Studies have consistently demonstrated an association between worsening renal function in ADHF and adverse outcomes. Adenosine A(1) receptor antagonists, such as rolofylline, appear in preliminary studies to produce potentially beneficial effects on natriuresis, diuresis, renal blood flow, and glomerular filtration rate. In a previous dose-finding study, rolofylline 30 mg intravenously daily for 3 days was associated with symptom improvement, less worsening of renal function, and trends toward lower 60-day rates of death or readmission for cardiovascular or renal causes. METHODS AND RESULTS: This manuscript describes the rationale underlying the design of the phase 3 PROTECT (Placebo-controlled Randomized study of the selective A(1) adenosine receptor antagonist rolofylline for patients hospitalized with acute heart failure and volume Overload to assess Treatment Effect on Congestion and renal funcTion) trial. CONCLUSION: Rolofylline 30 mg or matching placebo was given intravenously as a 4-hour continuous infusion on 3 consecutive days and the hospital course was assessed by measurements dyspnea, clinical status, renal function, and subsequent morbidity and mortality in a large population of patients with ADHF with renal impairment.

The importance of the clinical observer in the development of a white-coat effect in African-American patients with hypertension.

INTRODUCTION: As the office-awake blood pressure (BP) difference (white-coat effect) in African-Americans has not been evaluated, we studied the ethnicity, professional status (nurse versus doctor) and sex of the observer on the white-coat effect in African-American patients with hypertension. METHODS: Seated clinical BP measurements were obtained in random order by an African-American male research physician, a Caucasian male research physician, and a Caucasian female nurse who is of similar age and clinical experience. Within 1 week, ambulatory BP recordings were performed. RESULTS: A total of 65 African-American patients [54+/-13 years, 55% women, body mass index (BMI) 31+/-6 kg/m, 62% on drug therapy, 28% current smokers] participated in the study. Twenty-two percent had a systolic white-coat effect >20 mmHg and 49% had a diastolic white-coat effect >10 mmHg (average of all observers). Although there were no differences in the magnitude of the white-coat effect among the three study observers, the primary physician's diastolic white-coat effect was significantly greater than that of the African-American physician (14+/-12 vs. 9+/-12, P=0.05), but not the systolic white-coat effect (16+/-16 vs. 10+/-16 mmHg, P=0.09). BMI positively correlated with the systolic and diastolic white-coat effect (r=0.30, P=0.02 and r=0.41, P=0.0001), but this correlation was true only for female patients in multiple regression analyses. BMI significantly predicted the systolic (P=0.043) and diastolic (P=0.004) white-coat effects. CONCLUSION: A white-coat effect is relatively common in African-American patients with hypertension and is the largest when the observer is their usual doctor. The clinical observer's ethnicity or sex does not play an important role in generating a white-coat effect in African-American patients with hypertension.

Primary hyperaldosteronism associated with hypertensive emergencies.

There is growing awareness of primary hyperaldosteronism as a cause of secondary hypertension. Usually, it manifests as hypertension and hypokalemia, or as resistant hypertension. Much less often, primary hyperaldosteronism may be detected after a hypertensive emergency has developed. We highlight this association by reporting on eight patients with a clinical diagnosis of primary hyperaldosteronism whose course was complicated by a hypertensive crisis. In all patients, an elevated serum aldosterone, was accompanied by a suppressed plasma renin activity despite the presence of a hypertensive crisis. A good outcome was obtained either with laparoscopic adrenalectomy (1 patient) or with an antihypertensive drug regimen that included an antialdosterone agent (7 patients). The differential diagnosis of hypertensive emergencies should include primary hyperaldosteronism.

History of major depressive disorder and endothelial function in postmenopausal women.

OBJECTIVE: To determine whether history of depression is associated with endothelium-dependent flow-mediated dilation (FMD) in postmenopausal women. METHODS: Thirty-nine postmenopausal women with no known or suspected cardiovascular disease participated. Nineteen had a positive lifetime history of major depressive disorder, and 20 were never depressed. None were currently depressed, and all had been free of major depressive disorder and antidepressant medications for > or =1 year. History of depression was assessed with the Structured Clinical Interview for DSM-IV, enhanced by a modified version of the timeline follow-back method. Current depressive symptoms were measured with the Center for Epidemiological Studies Depression scale (CES-D). Brachial artery FMD was measured with ultrasound and calculated as percent dilation from baseline. RESULTS: After controlling for current subclinical depressive symptoms, ethnicity, hormone replacement therapy, and presence of the metabolic syndrome, previously depressed women showed significantly and clinically meaningful lower FMD than never depressed women. Controlling the same covariates, there was a dose-response relationship between number of depressive episodes and FMD. Examination of FMD means showed a significant negative correlation between number of depressive episodes and FMD. CONCLUSION: In postmenopausal women, depression continues to show a negative relationship to endothelial functioning even after years of remission. This relationship is not accounted for by residual depressive symptoms. Implications pertain to exclusion of previously depressed persons from control groups in research exploring the relationship between depression and cardiovascular disease.

Orthostatic hypotension due to autonomic disorders in the hypertension clinic.

Hypertension specialists are consulted regarding orthostatic hypotension (OH) or the combination of OH with supine hypertension. These clinical presentations are often associated with a variety of underlying autonomic disorders. A comprehensive medical history and clinical examination with attention to autonomic signs and the neurological system may suggest the possible etiology or a differential diagnosis. At times, drug therapy for hypertension or other diseases such as Parkinson's is temporally associated with the onset of OH. At other times, no definitive association can be made. Most hypertension specialists can initiate basic evaluation and treatment. Treatment approaches to OH must be targeted primarily to alleviate symptoms of cerebral hypoperfusion and also be cognizant of supine hypertension. Several lifestyle and drug therapies can ameliorate symptoms of OH. Short-acting antihypertensive therapy may be useful in controlling nocturnal supine hypertension.

Herbs and alternative therapies: relevance to hypertension and cardiovascular diseases.

Herbal remedies, supplements, and alternative therapeutic items are used by many patients with hypertension and cardiovascular diseases. Scientific knowledge about their efficacy and safety is lacking, and unfortunately, physicians are frequently not aware that patients are using these nontraditional forms of medical care. Patients may anticipate physicians' disapproval of their use, or not realize that it is important for the physician to know what they are taking. Therefore, it is imperative that patients are asked nonjudgmental questions about current and past use of herbals and alternative therapies. Even when physicians are aware of such use, they feel poorly trained to identify the constituents and effects. Although many such therapies are innocuous, several herbal or alternative therapeutic items can significantly elevate blood pressure or cause interactions with cardiovascular drugs. Practitioners in cardiovascular medicine should be competent and know current scientific evidence for the benefits and adverse effects of herbal supplements and provide patients reasonable advice. In this brief article, we review the epidemiology of alternative therapy use, and select several important herbal or other supplements that patients with hypertension and cardiovascular diseases may be taking. We discuss the therapies considered biological in nature as opposed to mind-body interventions or manipulative body or energy therapies.

Self-measured home blood pressure in predicting ambulatory hypertension.

BACKGROUND: Physicians are commonly uncertain whether a person with office blood pressure (BP) around 140/90 mm Hg actually has hypertension. This is primarily because of BP variability. One approach is to perform self-measured home BP and determine if home BP is elevated. There is a general agreement that if home BP is >/=135/85 mm Hg, then antihypertensive therapy may be commenced. However, some persons with home BP below this cut-off will have ambulatory hypertension. We therefore prospectively study the role of home BP in predicting ambulatory hypertension in persons with stage 1 and borderline hypertension. METHODS: We studied in a cross-sectional way home and ambulatory BP in a group of 48 patients with at least two elevated office BP readings. The group was free of antihypertensive drug therapy for at least 4 weeks and performed 7 days of standardized self-BP measurements at home. We examined the relationships of the three BP methods and also defined a threshold (using receiver operating curves) for home BP that captures 80% of ambulatory hypertensives (awake BP >/=135/85 mm Hg). RESULTS: Office systolic BP (145 +/- 13 mm Hg) was significantly higher than awake (139 +/- 12 mm Hg, P = .013) and home (132 +/- 11 mm Hg, P < .001) BP. Office diastolic BP (88 +/- 4 mm Hg) was higher than home diastolic BP (80 +/- 8 mm Hg, P < .001) but not different from awake diastolic BP (88 +/- 8 mm Hg, P = .10). Home BP had a higher correlation (compared with office BP) with ambulatory BP. The home BP-based white coat effect correlated with ambulatory BP-based white coat effect (r = 0.83, P = .001 for systolic BP; r = 0.68, P = .001 for diastolic BP). The threshold for home BP of 80% sensitivity in capturing ambulatory hypertension was 125/76 mm Hg. CONCLUSIONS: Our preliminary data suggest that a lower self-monitored home BP threshold should be used (to exclude ambulatory hypertension) in patients with borderline office hypertension.

Effect of spironolactone on endothelial function in patients with congestive heart failure on conventional medical therapy.

We prospectively studied the effect of spironolactone, an aldosterone antagonist, on endothelial function in patients with advanced congestive heart failure (CHF) using the brachial artery reactivity method. Twenty patients optimized on conventional CHF therapy were treated with spironolactone, and brachial artery flow- mediated dilation was measured at baseline and at 4 and 8 weeks. Spironolactone improved endothelial function at 4 weeks, and sustained the improvement at 8 weeks, in patients with CHF on conventional medical therapy, presumably due to reversal of aldosterone impairment of endothelial nitric oxide activity.

The use of peridialysis blood pressure and intradialytic blood pressure changes in the prediction of interdialytic blood pressure in haemodialysis patients.

OBJECTIVE: It is uncertain which blood pressure values (pre- or post-haemodialysis) best represent the average daily blood pressure in haemodialysis patients. The purpose of this study was to verify the power of peridialysis blood pressure to predict interdialytic blood pressure, and to ascertain the influence of blood pressure fluctuations during dialysis on this predictive ability. METHODS AND RESULTS: We performed ambulatory blood pressure monitoring during the interdialytic period on 60 stable haemodialysis patients (mean age 53 +/- 16 years, 33 male) between two mid-week haemodialysis sessions. Pre- and post-haemodialysis blood pressures were 154/82 and 142/77 mmHg, respectively, and 44-h interdialytic blood pressure was 136/77 mmHg. Overall, post-haemodialysis blood pressure values correlated with interdialytic ambulatory blood pressure marginally better than did pre-haemodialysis values (r = 0.52 versus 0.61 for pre- and post-dialysis systolic pressure, respectively; r = 0.67 versus 0.72 for pre- and post-dialysis diastolic pressure, respectively). The average of the pre- and post-haemodialysis values showed a slightly better correlation with interdialytic blood pressure (r = 0.65 and 0.75 for systolic and diastolic pressure, respectively). When we stratified patients according to systolic blood pressure behaviour during dialysis, pre-dialysis blood pressure was the stronger predictor of interdialytic blood pressure in the quartile with greatest intradialytic blood pressure fall (r = 0.67 versus 0.44 for pre- and post-dialysis systolic blood pressure, respectively), whereas post-dialysis values were substantially better in the group with a rise in systolic pressure during dialysis (r = 0.26 versus 0.59 for pre- and post-dialysis systolic blood pressure, respectively). CONCLUSIONS: These data demonstrate that peridialysis blood pressure values are of limited accuracy in predicting interdialytic blood pressure, post-dialysis values are minimally better predictors than pre-dialysis blood pressures, and the average of pre- and post-haemodialysis values is marginally better than both. In addition, blood pressure fluctuations during dialysis have a sizable impact on this predictive ability. Clinical decisions related to blood pressure management and research design in haemodialysis hypertension should take these factors into account.

Blood pressure control in the hypertension clinic.

BACKGROUND: One effort to improve hypertension care in the United States is the development of the "Hypertension Specialist" program with appropriate training and certification of individual physicians. METHODS: We examined the impact of a hypertension clinic on blood pressure (BP) levels and control. RESULTS: By one year, BP declined 18/9 mm Hg, (P =.001) and BP control rates increased from 26% to 55% (P <.001) for systolic BP, from 47% to 82% (P <.001) for diastolic BP and from 18% to 52% (P <.001) for both. Age and systolic BP were significantly higher in uncontrolled patients. CONCLUSIONS: Attendance in a hypertension clinic significantly impacts BP control.